Discriminative Stimulus Properties of S32504, a Novel D3/D2 Receptor Agonist and Antiparkinson Agent, in Rats: Attenuation by the Antipsychotics, Aripiprazole, Bifeprunox, N-desmethylclozapine, and by Selective Antagonists at Dopamine D2 but Not D3...

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2006 Oct 19

PMID 17047933

Citations 8

Authors

Mark J Millan

Loretta Iob

Jean-Louis Peglion

Anne Dekeyne

Affiliations

Soon will be listed here.

Abstract

Rationale: Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D(3) and (less potently) D(2) receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther 309:936-950, 2004a; Millan et al., J Pharmacol Exp Ther 309:903-920, 2004b; Millan et al., J Pharmacol Exp Ther 309:921-935, 2004c).

Objectives: To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents.

Materials And Methods: Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline.

Results: S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (+/-) S31411, and to its inactive (-) distomer, S32601. Apomorphine, and the selective D(3)/D(2) receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D(4) and D(1)/D(5) receptor agonists were ineffective. The selective D(3) vs D(2) receptor partial agonist, BP897, did not substitute for S32504 and the selective D(3) receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504 lever selection was blocked by the preferential D(2) vs D(3) receptor antagonists, L741,626 and S23199, and by the D(2)/D(3) antagonists, raclopride and haloperidol. The D(2)/D(3) receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties.

Conclusion: The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D(2) receptors Antipsychotics known to act as partial agonists at D(2)/D(3) receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites.

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References

Reavill C, Taylor S, Wood M, Ashmeade T, Austin N, Avenell K . Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J Pharmacol Exp Ther. 2000; 294(3):1154-65. View

Bruins Slot L, De Vries L, Newman-Tancredi A, Cussac D . Differential profile of antipsychotics at serotonin 5-HT1A and dopamine D2S receptors coupled to extracellular signal-regulated kinase. Eur J Pharmacol. 2006; 534(1-3):63-70. DOI: 10.1016/j.ejphar.2006.01.027. View

Beardsley P, Sokoloff P, Balster R, Schwartz J . The D3R partial agonist, BP 897, attenuates the discriminative stimulus effects of cocaine and D-amphetamine and is not self-administered. Behav Pharmacol. 2001; 12(1):1-11. DOI: 10.1097/00008877-200102000-00001. View

Millan M, Gobert A, Newman-Tancredi A, Lejeune F, Cussac D, Rivet J . S33084, a novel, potent, selective, and competitive antagonist at dopamine D(3)-receptors: I. Receptorial, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther. 2000; 293(3):1048-62. View

Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E . The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets. 2006; 5(1):25-43. DOI: 10.2174/187152706784111551. View

Perachon S, Betancur C, Pilon C, Rostene W, Schwartz J, Sokoloff P . Role of dopamine D3 receptors in thermoregulation: a reappraisal. Neuroreport. 2000; 11(1):221-5. DOI: 10.1097/00001756-200001170-00044. View

Dekeyne A, Millan M . Discriminative stimulus properties of antidepressant agents: a review. Behav Pharmacol. 2003; 14(5-6):391-407. DOI: 10.1097/01.fbp.0000089141.24369.07. View

Dekeyne A, Rivet J, Gobert A, Millan M . Generalization of serotonin (5-HT)1A agonists and the antipsychotics, clozapine, ziprasidone and S16924, but not haloperidol, to the discriminative stimuli elicited by PD128,907 and 7-OH-DPAT. Neuropharmacology. 2001; 40(7):899-910. DOI: 10.1016/s0028-3908(01)00022-3. View

Pillai G, Brown N, McAllister G, Milligan G, Seabrook G . Human D2 and D4 dopamine receptors couple through betagamma G-protein subunits to inwardly rectifying K+ channels (GIRK1) in a Xenopus oocyte expression system: selective antagonism by L-741,626 and L-745,870 respectively. Neuropharmacology. 1998; 37(8):983-7. DOI: 10.1016/s0028-3908(98)00092-6. View

10.

Baker L, Hood C, Heidema A . Assessment of D3 versus D2 receptor modulation of the discriminative stimulus effects of (+)-7-OH-DPAT in rats. Behav Pharmacol. 2000; 10(8):717-22. DOI: 10.1097/00008877-199912000-00002. View

11.

Cussac D, Newman-Tancredi A, Pasteau V, Millan M . Human dopamine D(3) receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. Mol Pharmacol. 1999; 56(5):1025-30. DOI: 10.1124/mol.56.5.1025. View

12.

Lelas S, Spealman R, Rowlett J . Using behavior to elucidate receptor mechanisms: a review of the discriminative stimulus effects of benzodiazepines. Exp Clin Psychopharmacol. 2000; 8(3):294-311. DOI: 10.1037//1064-1297.8.3.294. View

13.

Newman-Tancredi A, Cussac D, Audinot V, Nicolas J, De Ceuninck F, Boutin J . Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor. J Pharmacol Exp Ther. 2002; 303(2):805-14. DOI: 10.1124/jpet.102.039875. View

14.

Ybema C, Olivier B, Mos J, Tulp M, Slangen J . Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan. Eur J Pharmacol. 1994; 256(2):141-7. DOI: 10.1016/0014-2999(94)90238-0. View

15.

Goudie A, Baker L, Smith J, Prus A, Svensson K, Wong E . Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms. Behav Pharmacol. 2001; 12(5):303-15. DOI: 10.1097/00008877-200109000-00001. View

16.

Cunningham K, Callahan P, Appel J . Dopamine D1 receptor mediation of the discriminative stimulus properties of SKF 38393. Eur J Pharmacol. 1985; 119(1-2):121-5. DOI: 10.1016/0014-2999(85)90330-9. View

17.

Maggio R, Scarselli M, Novi F, Millan M, Corsini G . Potent activation of dopamine D3/D2 heterodimers by the antiparkinsonian agents, S32504, pramipexole and ropinirole. J Neurochem. 2003; 87(3):631-41. DOI: 10.1046/j.1471-4159.2003.02038.x. View

18.

Kamien J, Goldberg L, Woolverton W . Discriminative stimulus properties of D1 and D2 dopamine agonists in rats. J Pharmacol Exp Ther. 1987; 242(3):804-11. View

19.

Callahan P, Cunningham K . Discriminative stimulus properties of cocaine in relation to dopamine D2 receptor function in rats. J Pharmacol Exp Ther. 1993; 266(2):585-92. View

20.

Sanger D, Depoortere R, Perrault G . Discriminative stimulus effects of apomorphine and 7-OH-DPAT: a potential role for dopamine D3 receptors. Psychopharmacology (Berl). 1997; 130(4):387-95. DOI: 10.1007/s002130050255. View